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Departments of Endocrinology (J.W.A.S., C.F.A.E.-R., E.P.M.C., A.M.P., J.A.R.), Clinical Chemistry (M.F.), and Cardiology (G.B.B., E.R.H., E.E.v.d.W., J.J.B.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Address all correspondence and requests for reprints to: J. W. A. Smit, M.D., Ph.D., Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. E-mail: jwasmit{at}lumc.nl.
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Abstract |
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Objective: Our objective was to investigate the presence and reversibility of cardiac abnormalities in patients with long-term exogenous subclinical hyperthyroidism.
Design: We conducted a prospective, single-blinded, placebo-controlled randomized trial of 6 months duration with two parallel groups.
Setting: The study occurred at the Leiden University Medical Center, a tertiary referral center for thyroid carcinoma.
Patients: As a model for subclinical hyperthyroidism, 25 patients with a history of differentiated thyroid carcinoma with more than 10 yr of TSH suppressive therapy with L-T4 were studied.
Interventions: L-T4 dose was replaced by study medication containing L-T4 or placebo. Medication was titrated in a single-blinded fashion to establish continuation of TSH suppression (low-TSH group) or euthyroidism (euthyroid group).
Measurements: We assessed serum levels of free T4 and TSH and used echo Doppler cardiography including tissue Doppler to establish left ventricular (LV) dimensions and function as well as diastolic function. Baseline echocardiography data were compared with 24 controls.
Results: There were no differences in baseline cardiac parameters and TSH levels between the two groups. Although mean LV mass index was increased as compared with 24 controls, only four patients had LV hypertrophy at baseline. This was not improved by restoration of euthyroidism. At baseline, diastolic function was impaired in all patients as indicated by abnormal values for the peak flow of the early filling phase (E, 55.3 ± 9.5 mm/sec), the ratio of E and the peak flow of the atrial filling phase (E/A ratio, 0.87 ± 0.13), the early diastolic velocity obtained by tissue Doppler (E', 5.7 ± 1.3 cm/sec), and the peak atrial filling velocity obtained by tissue Doppler (A', 6.8 ± 1.4 cm/sec), prolonged E deceleration time (234 ± 34 msec), and isovolumetric relaxation time (121 ± 15 msec). After 6 months, significant improvements were observed in the euthyroid group in the E/A ratio (+41%; P < 0.001), E deceleration time (–18%; P = 0.006), isovolumetric relaxation time (–25%; P < 0.001), E' (+31%; P < 0.001), and the E'/A' ratio (+40%; P < 0.001).
Conclusions: We conclude that prolonged subclinical hyperthyroidism is accompanied by diastolic dysfunction that is at least partly reversible after restoration of euthyroidism. Because isolated diastolic dysfunction may be associated with increased mortality, this finding is of clinical significance.
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Introduction |
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The cardiovascular consequences of subclinical hyperthyroidism, defined by suppressed serum TSH levels despite normal free T4 and T3 concentrations, are less well established. However, the most consistent findings in endogenous subclinical hyperthyroidism include an increased heart rate, supraventricular arrhythmias, increased LV mass (LVM) with a slightly enhanced systolic function, and diastolic dysfunction (5, 6, 7, 8, 9). The interpretation of the cardiovascular consequences of endogenous subclinical hyperthyroidism is not straightforward. Most importantly, the duration and development in time of thyroid dysfunction are often not known. Second, it cannot be excluded that the underlying disease may influence cardiovascular parameters independent of serum T4 levels. Third, interventions to restore euthyroidism can hardly be performed in a randomized fashion.
Therefore the best model to study cardiac consequences of subclinical hyperthyroidism is exogenous subclinical hyperthyroidism, as is the case in athyreotic patients subjected to TSH-suppressive T4 therapy in the follow-up of differentiated thyroid carcinoma (DTC).
To date, six studies have been published on systolic and diastolic function in athyreotic patients with exogenous subclinical hyperthyroidism (10, 11, 12, 13, 14, 15). Four of these studies, all from one center, observed an increase in LVM and wall thickness as well as impairment in diastolic function. These studies, however, were performed in heterogeneous groups of patients (both DTC and multinodular goiter) who were treated with a TSH-suppressive dose of L-T4 for less than 10 yr. Most of the findings of these studies could not be confirmed in a study that solely contained athyreotic DTC patients (15).
In four of these studies, interventions were performed consisting of therapy with ß-blocking agents (10, 11, 13) or T4 dose titration (14). These interventions, nonrandomized and without control groups, resulted in significant improvements in left-ventricular dimensions and diastolic function.
We performed a prospective, randomized, placebo-controlled study in a homogeneous group of athyreotic DTC patients. Our aim was to investigate the reversibility of the effects of long-term (>10 yr) exogenous subclinical hyperthyroidism on systolic and diastolic cardiac function. We used echocardiography including tissue Doppler imaging (TDI) which allows for a detailed and quantitative assessment of cardiac parameters including diastolic and systolic function (16, 17).
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Subjects and Methods |
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Patients were recruited from the outpatient clinic of the Department of Endocrinology of Leiden University Medical Center. The Department of Endocrinology is a tertiary referral center for DTC. Patients were included who had been diagnosed with DTC and had received initial therapy consisting of total-thyroidectomy and radioiodine ablative therapy. Cure was documented by the absence of measurable serum thyroglobulin during TSH stimulation as well as by a negative total-body scintigraphy with 4 mCi 131I. The patients had to be on TSH-suppressive therapy, defined as TSH levels below the lower reference value for normal serum levels of TSH (0.4 mU/liter), for at least 10 yr. The adequacy of this therapy was documented by yearly TSH measurements.
No drugs known to influence cardiovascular parameters were allowed. None of the patients had hemodynamic instability, previous myocardial infarction, rheumatic fever, endocarditis, diabetes mellitus, or connective tissue disease. The study was approved by the local ethics committees, and written informed consent was obtained from all subjects.
Study design
The study was a prospective, single-blinded randomized study of 6 months duration with two parallel groups. After inclusion, patients were randomized in a single-blinded fashion (patients were blinded) to continuation of TSH-suppressive therapy (low-TSH group, target TSH level < 0.4 mU/liter) or restoration of euthyroidism by decreasing the L-T4 dose (euthyroid group, target TSH levels within the normal reference range of 0.40–4.8 mU/liter).
After randomization, the standard L-T4 therapy of all patients was replaced in part by study medication according to an algorithm. Study drugs consisted of either 25 µg T4 or placebo tablets with similar appearance. Serum TSH levels were checked every 6 wk in every patient, and study medication was adjusted if necessary to obtain the target TSH levels. Before and after 6 months, a physical examination was performed, and fasting blood samples were drawn for hormonal assessments. At each visit, heart rate, weight, and blood pressure were recorded and a compliance check was performed. Echocardiography was performed at baseline and after 6 months.
Echocardiography: data acquisition
Echocardiography was performed with the patients in the left lateral decubitus position using a commercially available system (Vingmed system FiVe/Vivid-7; General Electric-Vingmed, Milwaukee, WI). Standard parasternal (long- and short-axis) and apical views (2-, 4-, and 5-chamber) were obtained. Standard continuous-wave and pulse-wave Doppler examinations were performed. M-mode images were obtained from the parasternal long-axis views for quantitative assessment of LV dimensions, fractional shortening (FS), and LV ejection fraction (LVEF) (18). LVM was calculated by the cube formula and using the correction formula proposed by Devereux et al. (18): 0.8 x (1.04{[LVEDD + PWT + IVST]3 – [LVEDD]3}+ 0.6, where LVEDD is LV end diastolic diameter, PWT is posterior wall thickness, and IVST is interventricular septum thickness. LVM was corrected for body surface area to obtain LVM index (LVMI). LV hypertrophy was defined as LVMI > 120 g/m2 for men and > 116 g/m2 for women (19). Systolic function was evaluated by measurements of FS and LVEF (18, 20).
The following parameters of diastolic function were measured: diastolic transmitral peak velocities (E and A wave), the E/A ratio, the isovolumetric relaxation time (IVRT), and the E deceleration time. Quantitative diastolic data were derived from TDI analysis. For TDI analysis, the digital cineloops were analyzed using commercial software (Echopac 6.1; General Electric-Vingmed). The sample volume (4 mm3) was placed in the LV basal portions of the anterior, inferior, septal, and lateral walls (using the two- and four-chamber images). The following parameters (mean values calculated from three consecutive beats) were derived: early diastolic velocity (E') and late diastolic velocity (A') and the E'/A' ratio. All echocardiographic examinations and analyses were performed by a single observer, blinded for treatment modalities. Baseline echocardiography parameters were compared with a control group, consisting of 24 subjects without cardiovascular morbidity: 21 females and three males, with a mean age 46 ± 9 yr. Reference values for LV dimensions and function and diastolic function were obtained from the literature (21, 22) and for tissue Doppler parameters from Ref.23 .
Assays
Serum free T4 concentration was measured on an IMx system (Abbott, Abbott Park, IL) (intraassay variability of 2.47–7.57% and interassay variability of 5.6–12.4% at different levels). Serum TSH was determined with on a Modular Analytics E-170 system (Roche Diagnostic Systems, Basel, Switzerland) (intraassay variability, 0.88–10.66%; interassay variability, 0.91–12.05%).
Statistical analysis
We have based the number of patients on the study of Fazio et al. (10), who found a pooled SD in changes in LVMI of 10.9 g/m2 (z = 2.57). With a power of 80% and an 
-value of 0.05, it can be calculated that 12 patients per group are needed to detect a difference in LVMI of 13 g/m2 .
Data are reported as mean ± SD. The effects of different conditions on outcome variables were compared within and between patients using the two-tailed Student’s t test for paired and independent samples, respectively. Data without normal distribution were analyzed using the Mann-Whitney U test or Wilcoxon test. Proportional data were analyzed using 
2. Differences were considered statistically significant at P < 0.05. The calculations were performed using SPSS for Windows (SPSS, Chicago, IL).
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Results |
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Thirty-three patients could be included (Fig. 1
). Four patients were withdrawn before randomization; one patient had to undergo intestinal surgery for colonic polyps, two patients withdrew because they found the protocol too demanding, and one patient did not attend the randomization visit. After randomization, three patients from the euthyroid group withdrew, one patient after 12 wk, from complaints of fatigue, headache, and diarrhea. The second patient left the study after 6 wk because she appeared to be pregnant. The third patient was excluded because of apparent noncompliance; despite lowering the T4 dose, serum free T4 levels increased throughout the study. One patient was excluded from the low-TSH group, also for noncompliance. The data from these eight patients were not included in any analysis. Thus, a total of 25 subjects completed the study, 13 in the low-TSH group and 12 in the euthyroid group (Table 1).
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Thyroid hormone levels are summarized in Table 2. T4 dose and TSH and free T4 concentrations were not different between groups at baseline. At the end of the study, TSH concentrations were significantly lower and T4 replacement dose and serum free T4 and serum free T3 concentrations significantly higher in the low-TSH group as compared with the euthyroid group. Interestingly, T4 dose in the low-TSH group after 6 months was significantly higher (177 µg/d) than at baseline (166 µg/d; P = 0.038), which was accompanied by a nonsignificant decrease in median serum TSH levels.
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LV dimensions and systolic function.
LVM, IVST, and PWT were higher in patients than in controls (Table 3). Although mean LVM was significantly higher than controls, only four subjects had LV hypertrophy according to the criteria mentioned in Subjects and Methods (19). FS and LVEF were lower in patients than in controls. There were no differences in baseline values of LV dimensions and systolic function between the two groups.
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and Fig. 2). However, LVEF, FS, and LV end systolic diameter (LVESD) improved in the euthyroid group, whereas no change was observed in the low-TSH group. Changes in LVEDD, LVESD, FS, and LVEF before and after 6 months differed significantly between the two groups.
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) and differed also from reference values from the literature. No differences in baseline values were observed in parameters of diastolic function between the two groups (Table 5).
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and Fig. 3). The E/A ratio increased to 1.18, which can be considered as a normal mean value.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We found that long-term subclinical hyperthyroidism has profound effects on cardiac diastolic function that are at least in part reversible after restoration of euthyroidism.
Although we found an increased LVMI at baseline, only four patients fulfilled the criteria for LV hypertrophy (19). LVMI was not reduced by a dose reduction of T4. In earlier studies, more profound LV hypertrophy was found that was reversed by ß-blocking agents (10, 11, 13). An explanation for this discrepancy may be that the studies of Biondi et al. (13) contained both thyroid carcinoma and multinodular goiter patients who were selected for open treatment with ß-blockade when overt complaints of hyperthyroidism were present. Another explanation can be that in our study, patients were included with TSH above 0.1 mU/liter; in both groups, four patients had TSH values at baseline between 0.1 and 0.4 mU/liter. However, the results of the study did not differ when patients with TSH greater than 0.1 and less than 0.4 mU/liter were not included in the analysis.
We found an improvement in systolic function (as measured by LVEF and FS) in the euthyroid group. However, because baseline values for LVEF and FS were within the reference ranges, the clinical significance of this finding is limited.
The most intriguing finding was the apparent diastolic dysfunction in our patient group. After T4 dose reduction, a significant and profound increase in the E/A ratio was observed, whereas the E/A ratio in the group with persistent TSH suppression was unaltered. This was confirmed with tissue Doppler investigation, demonstrating a significant increase in the initially low E', in the euthyroid group. A similar effect was observed for the IVRT, which was prolonged at baseline and improved in the euthyroid group. The finding of diastolic dysfunction is in line with observations in earlier studies in both endogenous (8) and exogenous hyperthyroidism (10, 13, 14) but not the study of Shapiro et al. (15) in which no diastolic dysfunction was found. In addition, in our study we demonstrated in a randomized, placebo-controlled design that diastolic dysfunction can be reversible, even after long-term subclinical hyperthyroidism. The clinical consequences of isolated diastolic dysfunction in subclinical hyperthyroidism at present are not entirely clear, but a comparison with isolated diastolic dysfunction in other conditions suggests that it may be associated with increased morbidity and mortality and as such is of clinical relevance (24).
It has been suggested that the diastolic dysfunction in subclinical hyperthyroidism results from the increased LVM (25, 26) and that this effect counteracts the favorable effects of thyroid hormone on diastolic function (6, 27, 28). However, in our study, no important increase in LVM was found. It is more likely that biochemical effects of thyroid hormone on myocardial function are involved, unrelated to LVMI (5). The findings of this study add to the understanding of the negative cardiac effects of subclinical hyperthyroidism and also underline that restoration of euthyroidism, even after long-term subclinical hyperthyroidism, is beneficial.
Most patients who have undergone successful initial therapy for DTC will receive long-term TSH-suppressive treatment with L-T4. Although the rationale for this therapy is based on the supposed harmful effects of TSH (29, 30), the question arises whether long-term TSH-suppressive therapy is necessary in all patients. Two studies failed to demonstrate a clear preventive effect of TSH suppression on tumor recurrence or progression (31, 32). In addition, potential harmful effects of long-term TSH suppression have gained attention in a number of studies. The findings of the present study support the recommendations of a recent European Consensus Meeting on thyroid cancer (33) not to treat all patients with TSH-suppressive T4 replacement therapy unconditionally.
We conclude that prolonged subclinical hyperthyroidism is accompanied by important diastolic dysfunction that is at least partly reversible. These findings have important implications, both for the understanding of the cardiac consequences of prolonged subclinical hyperthyroidism and for the management of DTC in the long term.
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Footnotes |
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Abbreviations: A, Peak flow of the atrial filling phase; A', peak atrial filling velocity by TDI; DTC, differentiated thyroid carcinoma; E, peak flow of the early filling phase; E', early diastolic velocity by TDI; FS, fractional shortening; IVRT, isovolumetric relaxation time; IVST, interventricular septum thickness; LV, left ventricular; LVEDD, LV end diastolic diameter; LVEF, LV ejection fraction; LVESD, LV end systolic diameter; LVM, LV mass; LVMI, LVM index; PWT, posterior wall thickness; TDI, tissue Doppler imaging.
Received March 21, 2005.
Accepted August 18, 2005.
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